PROJECT SUMMARY Cognitive impairment is a frequent comorbidity affecting 75% of people with epilepsy including patients with Dravet syndrome (DS), a severe-infantile-onset epileptic encephalopathy characterized by frequent, prolonged seizures and numerous co-morbidities resulting from loss-of-function mutations in the voltage-gated sodium channel gene SCN1A. Current drug therapies are ineffective at controlling seizures and no therapy exists for severe cognitive deficits. While seizure frequency and severity often improves, children with DS who survive into their teenage years have IQs in the severely impaired range, 50 to 70, and typically require permanent institutional or family care. Therapy for cognitive impairment would dramatically improve the lives of these patients, substantially reduce long-term care costs, and reduce accidental deaths. Work in genetic mouse models, which are faithful genocopies and phenocopies, shows that inhibitory interneuron but not excitatory cell activity is impaired resulting in an in-balance between excitation and inhibition, the likely cause of seizures and co-morbidities. An emerging principle from systems-level neuroscience is that cognition depends on precisely timed electrophysiologic patterns, brain rhythms. Whether disrupted brain rhythms contribute to cognitive impairment in human disease, and whether interventions targeted at normalization of rhythms, through pharmaceuticals, targeted stimulation, or via correction of genetic defect, are a reasonable therapeutic strategy remains to be determined. Hippocampal sharp - wave / ripple (SWR) complexes contribute to spatial learning and memory and require high frequency, temporally precise action potential firing in inhibitory interneurons. We hypothesize that: Decreased SWR recurrence and slowed intra-ripple frequency are caused by hippocampal interneuron hypoexcitability and contribute to spatial memory impairment in DS mice. The proposed experiments will: (1) extend the preliminary finding of decreased ripple recurrence and slowed intra-ripple frequency in DS mice comparing SWR features by sleep-wake state and during context- dependent spatial learning to determine if rate of SWR occurrence and intra-ripple frequency are correlated with Scn1a expression and memory performance, (2) determine whether spatial memory impairment is mediated through effects of reduced Scn1a expression, reduced Na current, and hypoexcitability of forebrain GABAergic interneurons, (3) determine whether seizures contribute to spatial memory impairment and altered SWR features, and (4) determine whether altered SWR features and impaired spatial memory can be normalized with restoration of Na channel expression. This work will be organized around the following specific aims: Aim 1: Dependence of SWR recurrence, intra-ripple frequency, and spatial memory impairment on Scn1a expression Aim 2: Contribution of seizures to reduced SWR occurrence, slowed intra-ripple frequency, and spatial memory impairment